Development of an Adenosine A1 Receptor agonist, MRS5474 for the treatment of chronic depression Project Summary Depression is a common mental disorder, which can be chronic or recurrent, markedly tarnishing a person?s ability to function in their normal life. People with a depression can feel empty, sad, helpless, restless, hopeless, anxious, worthless, guilty, irritable, ashamed or suicidal. They may lose interest in routine work or physical activities. They show appetite disorder, problems concentrating, remembering details or making decisions. It has also been shown that healthy people may exhibit sub-clinical levels of depressive symptoms. Because of their impact on the society and widespread prevalence, depressive symptoms are a significant public health concern. Nearly 20% of the population, show depression-like symptoms at some point in their lives. Currently, there are 350 million people worldwide and 16 million people in the US affected by depression, and the scope of the population affected by depression is gradually expanding. The estimated market for antidepressants was $14.51 billion and will grow to $16.8 billion by the year 2020. Despite recent advances in pathophysiological hypotheses such as alterations in neuroplasticity, neurogenesis, and neuroimmunological regulation, current treatments lack rapid clinical efficacy limiting the ability, for example, to bring instant relief needed with suicidal patients. Therefore, there is a need for the rapid treatment of depression. The adenosine signaling pathway activated by sleep deprivation has shown rapid benefits in preclinical and clinical studies. In particular, sleep deprivation upregulates adenosine A1 receptors (A1R) in mice and humans. Dr. Jacobson and his group have identified a compound MRS5474 as a potent small- molecule A1R agonist with exceptional drug-like properties. It is metabolically stable, orally bioavailable and has an excellent safety profile in mice. Our collaborator, Dr. Biber, has shown that A1R knockout mice exhibit an increased depressive-like behavior and were resistant to the antidepressant effects of sleep deprivation. In contrast, he demonstrated that upregulation of A1R had pronounced acute and chronic resilience toward depressive- like behavior in various tests. Furthermore, they also showed that increased expression of homer1a is a final common pathway mediating the antidepressant effects of different antidepressant treatments including the A1R agonist. The A1R agonist MRS5474 induced a rapid antidepressant effects in animal models of transgenic mice with intraperitoneal (IP) administration. In summary, MRS5474 has great potential to be a rapid, efficacious and safe antidepressant with a unique mechanism of action. The expression of Homer1a and ERK1,2 will serve as biomarkers for preclinical and clinical studies. In this Fast-Track proposal, we will first establish that 1) MRS5474 has good BBB penetration (Brain/Plasma ratio ? 1), 2) direct relationship between exposure of MRS5474 and effects on Homer1a expression levels and ERK activity, 3) A1R antidepressant effects of MRS5474 in the CDM with oral administration and 4) an excellent safety profile. In the Phase II, we will continue with IND enabling studies to ensure that MRS5474 has all the attributes to become a successful antidepressant drug and will file IND application for clinical trials.